The gpl20 and gp4l envelope glycoproteins of human immunodeficiency virus (HIV-1), the etiologic agent of acquired immunodeficiency syndrome (AIDS), play important roles in virus entry into target cells and in viral cytopathic effect. Since the HIV-1 envelope glycoproteins are exposed on the virion, they represent critical targets for therapeutic intervention and vaccine development. Mutagenic analysis has been instrumental in providing information about the functional and antigenic determinants of the HIV-1 envelope glycoproteins. The first two specific aims of this application are designed to supplant a merely descriptive model of HIV-1 envelope glycoprotein structure and function with a model defining the interaction of regions involved in gpl20-gp4l association and in the membrane fusion reaction, using revertant analysis. Both the labile gpl2O-gp4l association and the membrane fusion process represent attractive targets for intervention. The third specific aim addresses the poor immunogenicity of the native HIV-1 gpl20 glycoprotein with respect to elicitation of antibodies capable of neutralizing diverse HIV-1 strains. Deleted versions of the HIV-1 gpl20 glycoprotein with improved exposure of the neutralization epitopes near the CD4-binding region have been synthesized. The ability of these gpl20 variants to elicit more broadly neutralizing antibodies, relative to that of the wild-type glycoprotein, will be examined.